Aromatic dicarboxylic acid derivatives

ABSTRACT

Compounds of formula I  
                 
 
     wherein A, R 1  and R 2  are defined in the specification. These compounds are useful as HDAC inhibitors. Also disclosed are methods of making and using said compounds.

PRIORITY TO RELATED APPLICATIONS

[0001] This application is a Division of Ser. No. 10/167,677, filed Jun.11, 2002, which is now pending.

[0002] The invention relates to aromatic dicarboxylic acid derivatives,or pharmaceutically-acceptable salts thereof, which possessanti-cell-proliferation activity such as anti-tumor activity and areaccordingly useful in methods of treatment of humans and other animals.The invention also relates to processes for the manufacture of saiddicarboxylic acid derivatives, to pharmaceutical compositions containingthe derivatives and to their use in the treatment of cell-proliferationdisorders.

BACKGROUND OF THE INVENTION

[0003] Transcriptional regulation is a major event in celldifferentiation, proliferation, and apoptosis. Transcriptionalactivation of a set of genes determines cell destination and for thisreason transcription is tightly regulated by a variety of factors. Oneof its regulatory mechanisms involved in the process is an alteration inthe tertiary structure of DNA, which affects transcription by modulatingthe accessibility of transcription factors to their target DNA segments.Nucleosomal integrity is regulated by the acetylation status of the corehistones. In a hypoacetylated state, nucleosomes are tightly compactedand thus are nonpermissive for transcription. On the other hand,nucleosomes are relaxed by acetylation of the core histones, with theresult being permissiveness to transcription. The acetylation status ofthe histones is governed by the balance of the activities of histoneacetyl transferase (HAT) and histone deacetylase (HDAC). Recently, HDACinhibitors have been found to arrest growth and apoptosis in severaltypes of cancer cells, including colon cancer, T-cell lymphoma, anderythroleukemic cells. Given that apoptosis is a crucial factor forcancer progression, HDAC inhibitors are promising reagents for cancertherapy as effective inducers of apoptosis (Koyama, Y., et al., Blood 96(2000) 1490-1495). !

[0004] Several structural classes of HDAC inhibitors have beenidentified and are reviewed in Marks, P. M., et al., J. Natl. CancerInst. 92 (2000) 1210-1216. More specifically, WO 98/55449 and U.S. Pat.No. 5,369,108 report alkanoyl hydroxamates with HDAC inhibitoryactivity.

[0005] It has now been found that certain aromatic dicarboxylic acidderivatives are more potent inhibitors of cell-proliferation than thecompounds reported in the aforementioned references. Furthermore, thesecompounds have HDAC inhibitiory activity.

DESCRIPTION OF THE INVENTION

[0006] The invention is directed to an aromatic dicarboxylic acidderivative of the formula I

[0007] denotes a phenyl ring which may be unsubstituted or substitutedby 1, 2 or 3 substituents independently selected from a halogen atom, an(1-4C)alkyl-, trifluoromethyl-, hydroxy-, (1-4C)alkoxy-, nitro-, amino-,(1-4C)alkylamino-, di[(1-4C)alkyl]-amino-, (1-4C)alkanoylamino, a(1-3C)alkylenedioxy-group or an acyl group, or alternatively,

[0008] denotes a thiophene ring which may be unsubstituted orsubstituted by 1 or 2 substituents independently selected from a halogenatom, an (1-4C)alkyl-, trifluoromethyl-, hydroxy-, (1-4C)alkoxy-,nitro-, amino-, (1-4C)alkylamino-, di[(1-4C)alkyl]-amino- or a(1-4C)alkanoylamino, a (1-3C)alkylenedioxy-group or an acyl group,

[0009]  and

[0010] R1 and R2 are each independently selected from

[0011] a hydrogen atom;

[0012] a branched or unbranched (1-14C)alkyl group, which

[0013] may be unsubstituted or substituted with 1 or severalsubstituents independently selected from the group consisting of ahalogen-, hydroxy-, nitro-, amino-, carbocyclic- or a heterocyclicgroup,

[0014] and wherein at a chain length of larger than 2 C-atoms one orseveral non adjacent C-atoms may be replaced by a corresponding numberof heteroatoms such as oxygen, nitrogen or sulfur,

[0015] and wherein 2 C-atoms may be bound together by a double or triplebond;

[0016] a carbocyclic group;

[0017] or a heterocyclic group;

[0018] or alternatively, R1 and R2 together with the nitrogen atom towhich they are attached form a 3-6 membered ring that may containadditional heteroatoms independently selected from nitrogen, oxygen andsulfur, said ring optionally being annulated to a carbocyclic ring or aheterocyclic ring, said —NR1R² ring being unsubstituted or optionallysubstituted by 1, 2, or 3 substituents independently selected from ahalogen atom, an (1-4C)alkyl-, trifluoro-methyl-, hydroxy-,(1-4C)alkoxy-, aryl-, hetaryl-, arylalkyl, arylalkyloxy-, aryloxy,(1-3C)alkylenedioxy-, nitro-, amino-, (1-4C)alkylamino-,di[(1-4C)alkyl]amino-, (1-4C)alkanoylamino- or an acyl-group.

[0019] An alkyl group may be e.g. pentyl, hexyl or 3-methyl-butyl.

[0020] A substituted alkyl group may be e.g. benzyl, phenethyl,tetrahydro-furan-2-yl-methyl or 2-cyclohex-1-enyl-ethyl.

[0021] An alkyl group where one or several non adjacent atom groups maybe replaced by oxygen, nitrogen or sulfur atoms may be e.g.3-isopropoxy-propyl or 2-methylsulfanyl-ethyl.

[0022] An alkyl group wherein 2 atoms may be bound together by a doubleor triple bond may be e.g. 1-hexinyl or 2-heptenyl.

[0023] “Annulated” as used herein means the fusion of a new ring to amolecule via two new bonds.

[0024] A carbocyclic group is a non-aromatic ring system having 3-7carbon ring atoms, for example cyclopentane, cyclohexane, cyclohexene orcyclopropane, said ring system being unsubstituted or optionallysubstituted by 1, 2, or 3 substituents independently selected fromhalogen, (1-4C)alkyl-, trifluoro-methyl-, hydroxy-, (1-4C)alkoxy-,aryl-, hetaryl-, arylalkyl, arylalkyloxy-, aryloxy,(1-3C)alkylenedioxy-, nitro-, amino-, (1-4C)alkylamino-,di[(1-4C)alkyl]amino-, (1-4C)alkanoylamino- or an acyl-group. Said ringatoms optionally may be annulated to an aryl or hetaryl group, to forme.g. an indane or a tetraline. A carbocyclic group as herein defined maybe an aryl group.

[0025] An aryl group is a carbocyclic conjugated ring system, forexample phenyl, naphthyl, preferably phenyl, which may be unsubstitutedor substituted by 1, 2, or 3 substituents independently selected from ahalogen atom, an (1-4C)alkyl-, trifluoromethyl-, hydroxy-,(1-4C)alkoxy-, arylalkyloxy-, aryloxy, (1-3C)alkylenedioxy-, nitro-,amino-, (1-4C)alkylamino-, di[(1-4C)alkyl]amino-, (1-4C)alkanoylamino-,carboxyl-, carboxyalkyl- or an acyl-group.

[0026] A heterocyclic group is a non-aromatic ring system having 3-7ring atoms, said ring atoms comprising carbon atoms and one or twohetero atoms independently chosen from nitrogen, oxygen, and sulfur.Examples of heterocyclic groups include piperidino, morpholino,pyrrolidino and piperazino. Said ring system may be unsubstituted orsubstituted by 1, 2, or 3 substituents independently selected fromhalogen, (1-4C)alkyl-, trifluoro-methyl-, hydroxy-, (1-4C)alkoxy-,aryl-, hetaryl-, arylalkyl, arylalkyloxy-, aryloxy,(1-3C)alkylenedioxy-, nitro-, amino-, (1-4C)alkylamino-,di[(1-4C)alkyl]amino-, (1-4C)alkanoylamino, or an acyl-group. Moreover,said ring atoms optionally may be annulated to an aryl or hetaryl group,to form e.g. a tetrahydrochinoline, tetrahydroisochinoline or adihydroindole. A heterocyclic group as defined herein also may be ahetaryl group.

[0027] A hetaryl group is either a 5 or 6 membered cyclic conjugatedring system with one or two hetero atoms independently chosen fromnitrogen, oxygen, and sulfur, for example pyridinyl, thiophenyl, furylor pyrrolyl, or an annulated bicydic conjugated ring system likeindolyl-, quinolyl- or isoquinolyl-, which may be unsubstituted orsubstituted by 1, 2, or 3 substituents independently selected from ahalogen atom, an (1-4C)alkyl-, trifluoro-methyl-, hydroxy-,(1-4C)alkoxy-, arylalkyloxy-, aryloxy, (1-3C)alkylenedioxy-, nitro-,amino-, (1-4C)alkylamino-, di[(1-4C)alkyl]amino-, (1-4C)alkanoylamino,or an acyl group.

[0028] When R1 and R2 together with the nitrogen atom form a 3-6membered ring which may contain additional heteroatoms independentlyselected from nitrogen, oxygen and sulfur, it may be e.g. piperidine,piperazine or morpholine.

[0029] A suitable value for a substituent when it is a halogen atom is,for example, fluoro, chloro, bromo and iodo; when it is (1-4C)alkyl is,for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl,sec-butyl; when it is (1-4C)alkoxy is, for example, methoxy, ethoxy,propoxy, isopropoxy or butoxy; when it is (1-4C)alkylamino is, forexample, methylamino, ethylamino or propylamino; when it isdi-[(1-4C)alkyl]amino is, for example, dimethylamino,N-ethyl-N-methylamino, diethylamino, N-methyl-N-propylamino ordipropylamino; when it is (1-4C)alkanoylamino is, for example,formylamido, acetamido, propionamido or butyramido; when it is(1-3C)alkylenedioxy is, for example, methylenedioxy, ethylenedioxy orpropylenedioxy; and when it is acyl is, for example, formyl, acetyl,propionyl, benzoyl, or phenylacetyl.

[0030] In a preferred embodiment, R1 is hydrogen and R2 has one of theabove values. In a more preferred embodiment, R2 is a (1-14C)alkylgroup. Most preferrably, R2 is an arylalkyl-radical, for example thebenzyl-radical or substituted benzyl-radicals.

[0031] Preferred are compounds wherin A denotes a thiophene ring. Evenmore preferred are compounds wherein the thiophene ring isunsubstituted. Most preferred are compounds wherin two carboxylicmoieties are bonded at positions 2 and 5 of a further unsubstitutedthiophene ring. Enantiomers, diastereoisomers, racemates and mixturesthereof and pharmaceutically acceptable salts of aromatic dicarboxylicacid derivatives of the formula I are also part of the invention.

[0032] The invention is also directed to a pharmaceutical compositioncomprising a therapeutically effective amount of an aromaticdicarboxylic acid derivative of the formula I, or apharmaceutically-acceptable salt thereof, as defined above, inassociation with a pharmaceutically-acceptable diluent or carrier. Thepharmaceutical composition may be in a form suitable for oraladministration, for example as a tablet or capsule, for parenteralinjection (including intravenous, subcutaneous, intramuscular,intravascular or infusion) as a sterile solution, suspension oremulsion, for topical administration as an ointment or cream or forrectal administration as a suppository. In general the abovecompositions may be prepared in a manner using conventional excipients.The aromatic dicarboxylic acid derivative will normally be administeredto a warm-blooded animal at a unit dose within the range 5-5000 mg persquare meter body area of the animal, i.e. approximately 0.1-100 mg/kg,and this normally provides a therapeutically-effective dose. A unit doseform such as a tablet or capsule will usually contain, for example 1-250mg of active ingredient. Preferably a daily dose in the range of 1-100mg/kg is employed. However the daily dose will necessarily be varieddepending upon the host treated, the particular route of administration,and the severity of the illness being treated. Accordingly the optimumdosage may be determined by the practitioner who is treating anyparticular patient.

[0033] According to a further aspect of the present invention there isprovided an aromatic dicarboxylic acid derivative of the formula I asdefined hereinbefore for use in a method of treatment of the human oranimal body by therapy. It has now been found that the compounds of thepresent invention possess anti-cell-proliferation properties due toinhibition of histone deacetylase. Accordingly the compounds of thepresent invention provide a method for treating the proliferation ofmalignant cells. These compounds are useful in the treatment of cancerby providing an anti-proliferative effect, particularly in the treatmentof cancers of the breast, lung, colon, rectum, stomach, prostate,bladder, pancreas and ovary. It is in addition expected that aderivative of the present invention will possess activity against arange of leukemias, lymphoid malignancies and solid tumors such ascarcinomas and sarcomas in tissues such as the liver, kidney, prostateand pancreas.

[0034] Thus according to this aspect of the invention there is providedthe use of an aromatic dicarboxylic acid derivative of the formula I, ora pharmaceutically-acceptable salt thereof, as defined herein in themanufacture of a medicament for use in the production of ananti-cell-proliferation effect in a warm-blooded animal such as a humanbeing.

[0035] According to a further feature of this aspect of the inventionthere is provided a method for producing an anti-cell-proliferationeffect in a warm-blooded animal, such as man, in need of such treatmentwhich comprises administering to said animal an effective amount of anaromatic dicarboxylic acid derivative as defined hereinbefore.

[0036] The anti-cell-proliferation treatment defined hereinbefore may beapplied as a sole therapy or may involve, in addition to the aromaticdicarboxylic acid derivative of the invention, one or more otheranti-tumor substances, for example those selected from, for example,mitotic inhibitors, for example vinblastine; alkylating agents, forexample cis-platin, carboplatin and cydophosphamide; inhibitors ofmicrotubule assembly, like paclitaxel or other taxanes; antimetabolites,for example 5-fluorouracil, capecitabine, cytosine arabinoside andhydroxyurea, or, for example, intercalating antibiotics, for exampleadriamycin and bleomycin; immunostimulants, for example trastuzumab; DNAsynthesis inhibitors, e.g. gemcitabine; enzymes, for exampleasparaginase; topoisomerase inhibitors, for example etoposide;biological response modifiers, for example interferon; andanti-hormones, for example antioestrogens such as tamoxifen or, forexample antiandrogens such as(4′-cyano-3-(4-fluorophenylsulphonyl)-2-hydroxy-2-methyl-3′-(trifluoromethyl)-propionanilide,or other therapeutic agents and principles as described in, for example,Cancer: Principles & Practice of Oncology, Vincent T. DeVita, Jr.,Samuel Hellmann, Steven A. Rosenberg; 5th Ed., Lippincott-RavenPublishers 1997. Such conjoint treatment may be achieved by way of thesimultaneous, sequential or separate dosing of individual components ofthe treatment. According to this aspect of the invention there isprovided a pharmaceutical product comprising an aromatic dicarboxylicacid derivative of the formula I as defined hereinbefore and anadditional anti-tumor substance as defined hereinbefore for the conjointtreatment of cancer.

[0037] Another object of the present invention is a pharmaceuticalcomposition containing a therapeutically effective amount of one or morecompounds of the invention in admixture with pharmaceutically acceptableexcipients and/or diluents.

[0038] Examples for physiologically acceptable salts of compounds offormula I are salts with physiologically acceptable bases. These saltscan be, among others, alkali, earth alkali, ammonium and alkylammoniumsalts, for example sodium, potassium, calcium, tetra-methyl-ammoniumsalts.

[0039] The compounds of formula I may exist in a racemic mixture. Theseparation of racemic compounds into their enantiomers can be performedby chromatography on an analytical, semipreparative or preparative scaleusing suitable optically active stationary phases with suitable eluents.Suitable optically active stationary phases include, but are not limitedto, silica (e.g. ChiraSper, Merck; Chiralpak OT/OP, Baker), celluloseesters or carbamates (e.g. Chiracel OB/OY, Baker) or others (e.g.Crownpak, Daicel or Chiracel OJ-R, Baker). Other methods for theseparation of enantiomers can also be applied, like the formation ofdiastereomeric compounds from compounds of the formula I together withother optically active compounds, e.g. camphorsulfonic acid or brucin,and separation of these diastereomeric compounds, followed by theliberation from the optically active agent. Enantiomerically enriched orpure compounds of formula I are also obtainable by the usage ofoptically active starting materials.

[0040] Preparation of the Compounds of the Invention

[0041] An aromatic dicarboxylic acid derivative of the formula I, or apharmaceutically-acceptable salt thereof, may be prepared by any processknown to be applicable to the preparation of chemically-relatedcompounds. Such processes, when used to prepare an aromatic dicarboxylicacid derivative of the formula I, or a pharmaceutically-acceptable saltthereof, are provided as a further feature of the invention and areillustrated by the following representative examples in which, unlessotherwise stated, A, R1 and R2 have any of the meanings defined above.Necessary starting materials may be obtained by standard procedures oforganic chemistry. The preparation of such starting materials isdescribed within the accompanying non-limiting examples. Alternativelynecessary starting materials are obtainable by analogous procedures tothose illustrated which are within the ordinary skill of an organicchemist.

[0042] (a) One preferred method for the production of compounds of theformula I involves the reaction of compounds of the formula II

[0043] wherein A, R1 and R2 have the meaning defined above and R3 is a(1-4C)alkyl group, preferably a methyl or ethyl group, withhydroxylamine in the presence of a suitable base. The reaction iscarried out in an inert solvent or diluent such as methanol or ethanolat temperatures between 0° C. and 100° C., conveniently at or nearambient temperature, and at a pH between 10 and 12. A suitable base is,for example, an alcoholate, for example, sodium methylate.

[0044] Compounds of formula II are prepared from compounds of theformula III wherein A and R3 have the meaning defined hereinbefore

[0045] This reaction typically involves a two-step one-pot procedure. Inthe first step, the carboxylate of the formula III becomes activated.This reaction is carried out in an inert solvent or diluent, forexample, in dichloromethane, dioxane, or tetrahydrofuran, in thepresence of an activating agent. A suitable reactive derivative of anacid is, for example, an acyl halide, for example an acyl chlorideformed by the reaction of the acid and an inorganic acid chloride, forexample thionyl chloride; a mixed anhydride, for example an anhydrideformed by the reaction of the acid and a chloroformate such as isobutylchloroformate; an active ester, for example an ester formed by thereaction of the acid and a phenol such as pentafluorophenol; an activeester formed by the reaction of the acid and N-hydroxybenzotriazole; anacyl azide, for example an azide formed by the reaction of the acid andan azide such as diphenylphosphoryl azide; an acyl cyanide, for examplea cyanide formed by the reaction of an acid and a cyanide such asdiethylphosphoryl cyanide; or the product of the reaction of the acidand a carbodiimide such as dicyclohexylcarbodiimide, or the product ofthe reaction of the acid andbis-(2-oxo-3-oxazolidinyl)-phosphorylchloride. The reaction is carriedout between −30° C. and 60° C., conveniently at or below 0° C. In thesecond step, an amine of the formula HNR1R2 in which R1 and R2 have themeaning defined hereinbefore is added to the solution, at thetemperature used for the activation, and the temperature is slowlyadjusted to ambient temperature. An appropriate scavenger base like e.g.triethylamine, or diisopropyethlyamine may be added to the reactionmixture. These methods are well known to those skilled in the art. Inprinciple, all methods for the synthesis of amides as used in peptidechemistry as described in e.g. “Methoden der organischen Chemie(Houben-Weyl)” Vol. XV/1 and XV/2 are also applicable.

[0046] There are quite a few compounds of formula III described in theliterature. For example, the prototypic terephthalic monomethylester isdescribed in e.g. Z. Phys. Chem.(Leipzig) 262 (3) (1981) 445-448. It isalso commercially available. Thiophene-2,5-dicarboxylic acid monomethylester is described in e.g. U.S. Pat. No. 2,680,731. These monoesters areusually prepared by selective saponification of the diester, but othermethod may be useful as well and are well known to those skilled in theart.

[0047] (b) Another preferred method for the preparation of compounds ofthe formula I is the deprotection of compounds of the formula IV

[0048] wherein Y is a suitable protecting group and A, R1 and R2 havethe meaning defined hereinbefore.

[0049] Compounds of the formula IV are new and included within the scopeof the present invention.

[0050] Suitable protecting groups may be the benzyl-, p-methoxybenzyl-,tert.butyloxy-carbonyl-, trityl-, or silyl groups such as thetrimethylsilyl- or dimethyl-tert.butylsilyl-group. The reactions carriedout depend on the type of the protecting group. When the protectinggroup is a benzyl- or p-methoxybenzyl group, the reaction carried out isa hydrogenolysis in an inert solvent such as an alcohol like methanol orethanol, in the presence of a noble metal catalyst such as palladium ona suitable carrier such as carbon, barium sulfate, or barium carbonate,at ambient temperature and pressure. When the protecting group is thetert.butyloxycarbonyl-, trityl-, or a silyl group such as thetrimethylsilyl- or dimethyl-tert.butylsilyl-group, the reaction iscarried out in the presence of acids at a temperature between −20° C.and 60° C., preferably between 0° C. and ambient temperature. The acidmay be a solution of hydrochloric acid in an inert solvent such asdiethyl ether or dioxane, or trifluoro acetic acid in dichloromethane.When the protecting group is a silyl group such as the trimethylsilyl ordimethyl-tert.butylsilyl group, the reaction can also be carried out inthe presence of a fluoride source such as sodium fluoride or tetrabutylammonium fluoride in an inert solvent such as dichloromethane. Notnecessarily all protecting groups Y are compatible with all groups R1 orR2. In cases where the features of these groups do not allow the usageof a certain protecting group, other protecting groups Y or othermethods of preparation need to be applied.

[0051] Compounds of formula IV are obtained from the reaction ofcompounds of formula V

[0052] with a compound of the formula VI

[0053] wherein Y is a suitable protecting group as described above. Thisreaction typically involves a two-step one-pot procedure. In the firststep, the carboxylate of the formula V becomes activated. This reactionis carried out in an inert solvent or diluent, for example, indichloromethane, dioxane, or tetrahydrofuran, in the presence of anactivating agent. A suitable reactive derivative of an acid is, forexample, an acyl halide, for example an acyl chloride formed by thereaction of the acid and an inorganic acid chloride, for example thionylchloride; a mixed anhydride, for example an anhydride formed by thereaction of the acid and a chloroformate such as isobutyl chloroformate;an active ester, for example an ester formed by the reaction of the acidand a phenol such as pentafluorophenol; an active ester formed by thereaction of the acid and N-hydroxybenzotriazole; an acyl azide, forexample an azide formed by the reaction of the acid and an azide such asdiphenylphosphoryl azide; an acyl cyanide, for example a cyanide formedby the reaction of an acid and a cyanide such as diethylphosphorylcyanide; or the product of the reaction of the acid and a carbodiimidesuch as dicyclohexylcarbodiimide, or the product of the reaction of theacid and bis-(2-oxo-3-oxazolidinyl)-phosphorylchloride. The reaction iscarried out between −30° C. and 60° C., conveniently at or below 0° C.In the second step, compound VI is added to the solution, at thetemperature used for the activation, and the temperature is slowlyadjusted to ambient temperature. These methods are well known to thoseskilled in the art. In principle, all methods for the synthesis ofamides as used in peptide chemistry as described in e.g. “Methoden derorganischen Chemie (Houben-Weyl)” Vol. XV/1 and XV/2 are alsoapplicable.

[0054] Compounds of the formula V are prepared from compounds of theformula II by hydrolysis. The conditions under which the hydrolysis iscarried out depend on the nature of the group R3. When R3 is a methyl orethyl group, the reaction is carried out in the presence of a base, forexample, lithium hydroxide, sodium hydroxide, or potassium hydroxide inan inert solvent or diluent, for example, in methanol or ethanol. WhenR3 is the tert.butyl group, the reaction is carried out in the presenceof an acid, for example, a solution of hydrochloric acid in an inertsolvent such as diethyl ether or dioxane, or trifluoroacetic acid indichloromethane. When R3 is the benzyl group, the reaction is carriedout by hydrogenolysis in the presence of a noble metal catalyst such aspalladium or platinum on a suitable carrier, such as carbon. Notnecessarily all methods of hydrolysis are compatible with all groups R1or R2. In cases where the features of these groups do not allow theusage of a certain method of hydrolysis, other methods of preparationneed to be applied.

[0055] (c) Another preferred method for the preparation of compounds ofthe formula I is the reaction of a compound of the formula V withhydroxylamine. This reaction typically involves a two-step one-potprocedure. In the first step, the carboxylate of the formula V becomesactivated. This reaction is carried out in an inert solvent or diluent,for example, in dichloromethane, dioxane, or tetrahydrofuran, in thepresence of an activating agent. A suitable reactive derivative of anacid is, for example, an acyl halide, for example an acyl chlorideformed by the reaction of the acid and an inorganic acid chloride, forexample thionyl chloride; a mixed anhydride, for example an anhydrideformed by the reaction of the acid and a chloroformate such as isobutylchloroformate; an active ester, for example an ester formed by thereaction of the acid and a phenol such as pentafluorophenol; an activeester formed by the reaction of the acid and N-hydroxybenzotriazole; anacyl azide, for example an azide formed by the reaction of the acid andan azide such as diphenylphosphoryl azide; an acyl cyanide, for examplea cyanide formed by the reaction of an acid and a cyanide such asdiethylphosphoryl cyanide; or the product of the reaction of the acidand a carbodiimide such as dicyclohexylcarbodiimide, or the product ofthe reaction of the acid andbis-(2-oxo-3-oxazolidinyl)-phosphorylchloride. The reaction is carriedout between −30° C. and 60° C., conveniently at or below 0° C. In thesecond step, hydroxylamine is added to the solution, at the temperatureused for the activation, and the temperature is slowly adjusted toambient temperature. These methods are well known to those skilled inthe art. In principle, all methods for the synthesis of amides as usedin peptide chemistry as described in e.g. “Methoden der organischenChemie (Houben-Weyl)” Vol. XV/1 and XV/2 are also applicable.

[0056] (d) Compounds of formula I can also be prepared with methods ofsolid phase supported synthesis. Terephthalic acid or2,5-thiophenedicarboxylic acid is reacted with a hydroxylamine moiety(—O—NH₂) bound to a resin, e.g. a Wang resin (Wang-O—NH₂ resin wassupplied by EMC microcollections, Tübingen) to form a resin-boundhydroxamic acid. The second carbonic acid moiety is reacted with anamine by standard methods of amide formation as described in e.g.“Methoden der organischen Chemie (Houben-Weyl)” Vol. XV/1 and XV/2.After this, the hydroxamic acid is liberated from the solid support.This can be done for example with TFA. The crude product can be purifiedby LC-MS, if necessary.

[0057] The invention will now be illustrated in the followingnon-limiting examples in which, unless otherwise stated:

[0058] (i) evaporations were carried out by rotary evaporation in vacuoand work-up procedures were carried out after removal of residual solidssuch as drying agents by filtration;

[0059] (ii) operations were carried out at ambient temperature, that isin the range 18-25° C. and under an atmosphere of an inert gas such asargon or nitrogen;

[0060] (iii) column chromatography (by the flash procedure) and highpressure liquid chromatography (HPLC) were performed on Merck Kieselgelsilica or Merck Lichroprep RP-18 reversed-phase silica obtained from E.Merck, Darmstadt, Germany;

[0061] (iv) yields are given for illustration only and are notnecessarily the maximum attainable;

[0062] (v) melting points were determined using a Mettler SP62 automaticmelting point apparatus, an oil-bath apparatus or a Kofler hot plateapparatus.

[0063] (vi) the structures of the end-products of the formula I wereconfirmed by nuclear (generally proton) magnetic resonance (NMR) andmass spectral techniques (Micromass Platform II machine using APCI orMicromass Platform ZMD using electrospray);

[0064] (vii) intermediates were not generally fully characterized andpurity was assessed by thin layer chromatography;

[0065] (viii) the examples were actually performed; and

[0066] (viv) the following abbreviations have been used:

[0067] DMF, N,N-dimethylformamide;

[0068] DMSO, dimethylsulphoxide;

[0069] THF, tetrahydrofuran;

[0070] MeOH, methanol;

[0071] HCl, hydrochloric acid;

[0072] NaH, sodium hydride

[0073] CH₂Cl₂, dichloromethane;

[0074] H₂SO₄, sulphuric acid

[0075] sat., saturated

[0076] sol., solution

[0077] rt, room temperature

[0078] eq, equivalent

EXAMPLE 1 Thiophene-2,5-dicarboxylic acid 2-hydroxyamide5-[(naphthalen-1-ylethyl)-amide] (1a)

[0079] 1.9 g Thiophene-2,5-dicarboxylic acid monomethyl ester and 1.2 mLN-methylmorpholine is dissolved in 20 mL of CH₂Cl₂ at −10° C. To thissolution is added 1.5 mL isobutyl chloroformate. After 10 min ofstirring, 1.7 mL 1-(aminomethyl)-naphthalene in 5 mL of CH₂Cl₂ is added.The cooling bath is removed and the reaction mixture is allowed to reachrt. After 90 min, 10 mL of water and 10 mL 2N HCl are added. The phasesare separated, and the organic phase is washed with water. Afterevaporation of the solvent there is obtained 4.4 g crude5-[(naphtalen-1-ylmethyl)-carbamoyl]-thiophene-2-carboxylic acid methylester (1b) which is purified by recrystalisation from ethylacetate,petrol ether, yielding 58%, mp 125° C.

[0080] To a solution of 550 mg hydroxylamine hydrochloride in 8 mL MeOHis added ⅔ of a solution of 275 mg of sodium in 8 mL of MeOH. To this, asolution of 1.30 g5-[(naphtalen-1-ylmethyl)-carbamoyl]-thiophene-2-carboxylic acid methylester (1b) in 30 mL MeOH is added, followed by the remaining sodiummethylate solution. After stirring for 4 h at rt the solvent isevaporated. 20 mL of water are added, acidified with 4 mL 50% aceticacid, and the precipitate is collected by filtration. After triturationwith THF there is obtained 0.76 g thiophene-2,5-dicarboxylic acid2-hydroxyamide 5-[(naphthalen-1-ylmethyl)-amide] (1a) as a white powder,mp 170° C.

EXAMPLE 2 Thiophene-2,5-dicarboxylic acid 2-hydroxyamide5-(4-trifluoromethyl-benzylamide) (2a)

[0081] 2a is prepared from thiophene-2,5-dicarboxylic acid monomethylester in an analogous manner to that described for the preparation of 1aexample 1. The last step yields 40% of thiophene-2,5-dicarboxylic acid2-hydroxyamide 5-(4-trifluoromethyl-benzylamide) (2a), mp. 172-174° C.

EXAMPLE 3 N-hydroxy-N′-naphthalen-1-ylmethyl-terephthalamide (3a)

[0082] 1 eq of Wang-O—NH₂ is shaken with 11 eq of terephthalic acid, 5.5eq N,N′-diisopropylcarbodiimide, 5.5 eq 1-hydroxybenzotriazole and 25 eqdiisopropylethylamine in DMF for 4 h at 25° C. After that, the resin iswashed with DMF (5 times), MeOH (3 times), THF (3 times), CH₂Cl₂ (3times) and diethylether (3 times). The resin is then shaken with 5 eqpentafluorophenyl trifluoroacetate and 10 eq pyridine. After that, theresin is washed with DMF (2 times), followed by CH₂Cl₂ (2 times),followed by diethylether (2 times). The resin is then shaken with 5 eqof naphtalenemethylamine, 10 eq of diisopropylethylamine and 1 eq of1-hydroxybenzotriazole. It is then shaken with 5 eq pentafluorophenyltrifluoroacetate and 10 eq pyridine. After that, the resin is washedwith DMF (2 times), followed by CH₂Cl₂ (2 times). To liberate theproduct from the solid support, the resin is shaken with 50% TFA in dryCH₂Cl₂ with 5% triisopropylsilane added at rt for 1 h. The liquid phaseis filtered, the resin washed with CH₂Cl₂ (3 times), and the combinedfiltrates are evaporated. The crude product is dissolved intert-butanol/H₂O (80:20) and freeze-dried. To neutralize any remainingTFA, 100 μL of a 25% NH₄OH-sol is added and freeze-dried, again. Theremaining solid is purified by preparative LC-MS toN-hydroxy-N′-naphthalen-1-ylmethyl-terephthalamide, MS (APCI): 321.1(M+1)

EXAMPLE 4

[0083] Thiophene-2,5-dicarboxylic acid2-(3-chloro-benzylamide)5-hydroxyamide (4a)

[0084] 9.0 g Thiophene-2,5-dicarboxylic acid monomethyl ester isrefluxed in 30 mL of thionylchloride until gas evolution has ceased. Themixture is evaporated and the residue is slowly added to a solution of10.3 g 3-chlorobenzylamine and 20 g triethylamine in 180 mL CH₂Cl₂ at 0°C. After 15 min the cooling bath is removed and the reaction mixture isallowed to reach rt. After 2 h it is quenched with water, the phases areseparated, and the aqueous phase is extracted with CH₂Cl₂. The combinedorganic phases are dried with Na₂SO₄ and evaporated yielding a crudeproduct. This is purified by recrystallisation from diethylether/heptaneyielding 13.9 g (93%) crude5-[(3-chlorobenzyl)-carbamoyl]-thiophene-2-carboxylic acid methyl ester(4b), mp 91-93° C. To a solution of 2.9 g hydroxylamine hydrochloride in45 mL MeOH is added 25 mL of a solution of 1.4 g sodium in 40 mL ofMeOH. To this, a solution of 6.4 g ester 4b in 30 mL MeOH is added,followed by the remaining 15 mL of the sodium methylate solution. Afterstirring for 3 h at rt the solution is acidified with 1N HCl and someethylacetate is added. Thiophene-2,5-dicarboxylic acid2-(3-chloro-benzylamide) 5-hydroxyamide (4a) precipitates as a whitesolid; 4.7 g, 73%, mp. 183° C.

EXAMPLE 5 Thiophene-2,5-dicarboxylic acid2-(3,5-dimethyl-benzylamide)5-hydroxyamide (5a)

[0085] 5a is prepared from thiophene-2,5-dicarboxylic acid monomethylester in an analogous manner to that described for the preparation of 4aexample 4. MS (APCI): 305.3 (M+1)

EXAMPLE 6 Thiophene-2,5-dicarboxylic acid 2-hexylamide 5-hydroxyamide(6a)

[0086] 6a is prepared from thiophene-2,5-dicarboxylic acid monomethylester in an analogous manner to that described for the preparation of 4aexample 4, mp 171-173° C.

EXAMPLE 7 Thiophene-2,4-dicarboxylic acid2-(3,5-dimethyl-benzylamide)4-hydroxyamide (7a)

[0087] 0.5 g 2-carboxy-thiophen-4-carboxylic acid ethyl ester (M. Janda,J. Srogl, M. Nemec, I. Stibor; Org. Prep. and Proced. Int. 3 (6)(1971)295.) and 0.67 g N′-(3-dimethylaminopropyl)-N-ethylcarbodiimid×HClare stirred in 50 mL DCM for 15 min. Then, 0.338 g3,5-dimethylbenzylamin are added and the mixture is stirred overnight.The solution is extracted with 2N HCl and water, then evaporated. Theresidue is titurated with isohexan, and the resulting crystals arefiltrated and air-dried, yielding 0.58 g (73%) crude5-(3,5-Dimethyl-benzylcarbamoyl)-thiophene-3-carboxylic acid ethyl ester(7b). This ester in converted to title compound by reaction withhydroxylamine hydrochloride in a manner similar to that described forthe conversion of 4b into 4a in example 4. After chromatography (silica,ethylacetate), thiophene-2,4-dicarboxylic acid2-(3,5-dimethyl-benzylamide)4-hydroxyamide (7a) is obtained as crystals;44 mg, 9%, mp: 181° C. (decomp.).

EXAMPLE 8 Thiophene-2,4-dicarboxylic acid2-(3-chloro-benzylamide)4-hydroxyamide (8a)

[0088] 8a is prepared from 2-carboxy-thiophen-4-carboxylic acid ethylester in an analogous manner to that described for the preparation of 7aexample 7; 163 mg, 34%, mp: 90° C. (decomp.).

EXAMPLE 9 Thiophene-2,4-dicarboxylic acid 4-hydroxyamide2-(4-trifluoromethyl-benzylamide) (9a)

[0089] 9a is prepared from 2-carboxy-thiophen-4-carboxylic acid ethylester in an analogous manner to that described for the preparation of 7aexample 7; 56 mg, 10%, mp: 174-177° C.

EXAMPLE 10 Thiophene-2,4-dicarboxylic acid 2-[(benzo[1,3]dioxol-5-ylmethyl)-amide]4-hydroxyamide (10a)

[0090] 10a is prepared from 2-carboxy-thiophen-4-carboxylic acid ethylester in an analogous manner to that described for the preparation of 7aexample 7; 16 mg, 3%, mp: 182° C. (decomp.).

EXAMPLE 11 Thiophene-2,4-dicarboxylic acid 2-hexylamide 4-hydroxyamide(11a)

[0091] 11a is prepared from 2-carboxy-thiophen-4-carboxylic acid ethylester in an analogous manner to that described for the preparation of 7aexample 7; 92 mg, 20%, mp: 150° C. (decomp.).

EXAMPLE 12 Thiophene-2,4-dicarboxylic acid4-(3,5-dimethyl-benzylamide)2-hydroxyamide (12a)

[0092] 5.0 g 2-carboxy-thiophen-4-carboxylic acid ethyl ester (Org.Prep. and Proced. Int. 3 (6) (1971) 295) is dissolved in 50 mL THF and4.5 g thionylchloride is added. After refluxing for 4 h, the mixture isevaporated. The crude acid chloride is added to a solution of 3.1 gO-benzylhydroxylamine and 3.06 g triethylamine in 80 mL DCM. Afterstirring for 4 h the solution is washed with 2N HCl and water, dried andevaporated. After titurating the residue with isohexan/diethylether,bright crystals of 5-benzyloxycarbamoyl-thiophene-3-carboxylic acidethyl ester (12b) are obtained, which are filtered and air-dried; 3.5 g,46%. 0.46 g NaOH are dissolved in 45 mL ethanol and 5 mL water. Theester 12b is added and the solution refluxed for 2 h. After cooling, theethanol is evaporated and the aqueous phase extracted with diethylether.The aqueous phase is acidified with 2N HCl and the precipitate formed iscollected by filtration, yielding 2.8 g (88%)5-benzyloxycarbamoyl-thiophene-3-carboxylic acid (12c) as a solid.

[0093] 0.4 g 5-benzyloxycarbamoyl-thiophene-3-carboxylic acid (12c) isdissolved in 50 mL DCM, and 0.387 gN′-(3-dimethylaminopropyl)-N-ethylcarbodiimid×HCl are added. Afterstirring for 15 min, 0.195 g 3,5-dimethylbenzylamine is added, and themixture is stirred overnight.

[0094] The solution is extracted with 2N HCl and water, then evaporated.The residue is titurated with ether/isohexan, and the resulting crystalsare filtrated and air-dried, yielding 0.44 g (77%) ofthiophene-2,4-dicarboxylic acid2-(benzyloxy-amide)4-(3,5-dimethyl-benzylamide) (12d). This ishydrogenated in a 1:1 mixture of THF and MeOH using Pd/CaSO₄/C andpurified by preparative HPLC/MS yielding 12a: MS (APCI): 303.1 (M−1).

EXAMPLE 13

[0095] In an analogous manner to that described in the example 12, thefollowing compounds are prepared:

[0096] 1. Thiophene-2,4-dicarboxylic acid4-(3-chloro-benzylamide)2-hydroxyamide

[0097] 2. Thiophene-2,4-dicarboxylic acid 4-hexylamide 2-hydroxyamide

EXAMPLE 144-{[(5-Hydroxycarbamoyl-thiophene-2-carbonyl)-amino]-methyl}-benzoicacid methyl ester

[0098] In an analogous manner to that described in the example 12, butusing 2-carboxy-thiophen-5-carboxylic acid methyl ester and methyl4-(aminomethyl)-benzoate as starting material,4-{[(5-Hydroxycarbamoyl-thiophene-2-carbonyl)-amino]-methyl}-benzoicacid methyl ester is prepared, mp.: 156-166° C.

EXAMPLE 15

[0099] In an analogous manner to that described in the example 1, andusing known methods as described in the literature (e.g. in standardworks such as Houben-Weyl, “Methoden der Organischen Chemie, GeorgThieme Verlag”, Stuttgart; Organic Reactions, John Wiley & Sons, Inc.,New York) the following compounds are prepared and characterized with MS(APCI):

[0100] 1. 5-(4-benzhydryl-piperazine-1-carbonyl)-thiophene-2-carboxylicacid hydroxyamide

[0101] 2. thiophene-2,5-dicarboxylic acid 2-benzylamide 5-hydroxyamide

[0102] 3. thiophene-2,5-dicarboxylic acid 2-hydroxyamide5-[(3-methyl-butyl)-amide]

[0103] 4. thiophene-2,5-dicarboxylic acid 2-hydroxyamide5-(phenethyl-amide)

[0104] 5. thiophene-2,5-dicarboxylic acid 2-hydroxyamide5-{[2-(4-methoxy-phenyl)-ethyl]-amide}

[0105] 6. thiophene-2,5-dicarboxylic acid2-(4-fluoro-benzylamide)5-hydroxyamide

[0106] 7. thiophene-2,5-dicarboxylic acid 2-hydroxyamide5-[(1,2,3,4-tetrahydro-naphthalen-1-yl)-amide]

[0107] 8. thiophene-2,5-dicarboxylic acid2-(2-ethoxy-benzylamide)5-hydroxyamide

[0108] 9. thiophene-2,5-dicarboxylic acid2-(2,4-difluoro-benzylamide)5-hydroxyamide

[0109] 10. thiophene-2,5-dicarboxylic acid 2-hydroxyamide5-indan-1-ylamide

[0110] 11. thiophene-2,5-dicarboxylic acid2-[(benzo[1,3]dioxol-5-ylmethyl)-amide]5-hydroxyamide

[0111] 12. 5-(4-phenyl-piperazine-1-carbonyl)-thiophene-2-carboxylicacid hydroxyamide

[0112] 13. thiophene-2,5-dicarboxylic acid 2-hydroxyamide5-[(3-isopropoxy-propyl)-amide]

[0113] 14. 5-(4-acetyl-piperazine-1-carbonyl)-thiophene-2-carboxylicacid hydroxyamide

[0114] 15. thiophene-2,5-dicarboxylic acid 2-dibutylamide 5-hydroxyamide

[0115] 16. 5-(4-benzyl-piperidine-1-carbonyl)-thiophene-2-carboxylicacid hydroxyamide

[0116] 17. thiophene-2,5-dicarboxylic acid 2-hydroxyamide5-[(pyridin-3-ylmethyl)-amide]

[0117] 18. thiophene-2,5-dicarboxylic acid 2-cyclohexylamide5-hydroxyamide

[0118] 19. thiophene-2,5-dicarboxylic acid 2-cyclopropylamide5-hydroxyamide

[0119] 20. thiophene-2,5-dicarboxylic acid 2-hydroxyamide5-{[2-(1-methyl-pyrrolidin-2-yl)-ethyl]-amide}

[0120] 21. thiophene-2,5-dicarboxylic acid 2-hydroxyamide5-(2-methoxy-benzylamide)

[0121] 22. thiophene-2,5-dicarboxylic acid2-[(2-cyclohex-1-enyl-ethyl)-amide]5-hydroxyamide

[0122] 23. thiophene-2,5-dicarboxylic acid 2-hydroxyamide5-[(2-morpholin-4-yl-ethyl)-amide]

[0123] 24. thiophene-2,5-dicarboxylic acid 2-hydroxyamide5-[(2-methylsulfanyl-ethyl)-amide]

[0124] 25. thiophene-2,5-dicarboxylic acid 2-hydroxyamide5-[(tetrahydro-furan-2-ylmethyl)-amide]

[0125] 26. thiophene-2,5-dicarboxylic acid 2-hydroxyamide 5-phenylamide

[0126] 27. 5-(morpholine-4-carbonyl)-thiophene-2-carboxylic acidhydroxyamide

[0127] 28. thiophene-2,5-dicarboxylic acid 2-hydroxyamide5-[(4-methoxy-phenyl)-amide]

[0128] 29. 5-(pyrrolidine-1-carbonyl)-thiophene-2-carboxylic acidhydroxyamide

[0129] 30. thiophene-2,5-dicarboxylic acid2-[(4-benzyloxy-phenyl)-amide]5-hydroxyamide

[0130] 31. thiophene-2,5-dicarboxylic acid2-[(4-chloro-phenyl)-amide]5-hydroxyamide

[0131] 32. thiophene-2,5-dicarboxylic acid 2-hydroxyamide5-[(4-iodo-phenyl)-amide]

[0132] 33. thiophene-2,5-dicarboxylic acid2-[(3-ethyl-phenyl)-amide]5-hydroxyamide

[0133] 34. thiophene-2,5-dicarboxylic acid2-[(4-ethyl-phenyl)-amide]5-hydroxyamide

[0134] 35. thiophene-2,5-dicarboxylic acid2-[(3-chloro-phenyl)-amide]5-hydroxyamide

[0135] 36. thiophene-2,5-dicarboxylic acid 2-hydroxyamide5-[(3-iodo-phenyl)-amide]

[0136] 37.5-(1,4-dioxa-8-aza-spiro[4.5]decane-8-carbonyl)-thiophene-2-carboxylicacid hydroxyamide

[0137] 38. thiophene-2,5-dicarboxylic acid 2-hydroxyamide5-[(3-morpholin-4-yl-propyl)-amide]

[0138] 39. thiophene-2,5-dicarboxylic acid 2-hydroxyamide 5-pentylamide

[0139] 40. thiophene-2,5-dicarboxylic acid2-[(2-diethylamino-ethyl)-amide]5-hydroxyamide

[0140] 41. thiophene-2,5-dicarboxylic acid 2-heptylamide 5-hydroxyamide

[0141] 42. thiophene-2,5-dicarboxylic acid 2-hydroxyamide5-(isobutyl-amide)

[0142] 43. thiophene-2,5-dicarboxylic acid 2-hydroxyamide 5-nonylamide

[0143] 44. thiophene-2,5-dicarboxylic acid 2-hydroxyamide5-[(1-phenyl-ethyl)-amide]

[0144] 45. thiophene-2,5-dicarboxylic acid2-[2-(4-fluoro-phenyl)-ethyl]-amide 5-hydroxyamide

[0145] 46. thiophene-2,5-dicarboxylic acid 2-hydroxyamide5-[2-(5-nitro-pyridin-2-ylamino)-ethyl]-amide

[0146] 47. thiophene-2,5-dicarboxylic acid 2-hydroxyamide5-(3-methyl-benzylamide)

[0147] 48. thiophene-2,5-dicarboxylic acid 2-hydroxyamide5-[(2-p-tolyl-ethyl)-amide]

[0148] 49. thiophene-2,5-dicarboxylic acid 2-hydroxyamide5-[3-(2-oxo-pyrrolidin-1-yl)-propyl]-amide

[0149] 50. thiophene-2,5-dicarboxylic acid 2-hydroxyamide5-[(2-piperidin-1-yl-ethyl)-amide]

[0150] 51. thiophene-2,5-dicarboxylic acid 2-cyclobutylamide5-hydroxyamide

[0151] 52. thiophene-2,5-dicarboxylic acid2-(2-fluoro-benzylamide)5-hydroxyamide

[0152] 53. thiophene-2,5-dicarboxylic acid 2-hydroxyamide5-[(2-phenyl-propyl)-amide]

[0153] 54. thiophene-2,5-dicarboxylic acid2-(2,3-dimethoxy-benzylamide)5-hydroxyamide

[0154] 55. thiophene-2,5-dicarboxylic acid2-[(1-benzyl-piperidin-4-yl)-amide]5-hydroxyamide

[0155] 56.4-[(5-hydroxycarbamoyl-thiophene-2-carbonyl)-amino]-piperidine-1-carboxylicacid ethyl ester

[0156] 57. thiophene-2,5-dicarboxylic acid2-[(3-dimethylamino-2,2-dimethyl-propyl)-amide]5-hydroxyamide

[0157] 58. thiophene-2,5-dicarboxylic acid2-[(3-ethoxy-propyl)-amide]5-hydroxyamide

[0158] 59. thiophene-2,5-dicarboxylic acid2-[(3-dimethylamino-propyl)-amide]5-58

[0159] 60. thiophene-2,5-dicarboxylic acid2-[2-(2-chloro-phenyl)-ethyl]-amide 5-hydroxyamide

[0160] 61. thiophene-2,5-dicarboxylic acid 2-hydroxyamide5-(2-trifluoromethyl-benzylamide)

[0161] 62. thiophene-2,5-dicarboxylic acid 2-hydroxyamide5-(3-trifluoromethyl-benzylamide)

[0162] 63. thiophene-2,5-dicarboxylic acid2-(2,5-difluoro-benzylamide)5-hydroxyamide

[0163] 64. thiophene-2,5-dicarboxylic acid2-(2,6-difluoro-benzylamide)5-hydroxyamide

[0164] 65. thiophene-2,5-dicarboxylic acid2-(3,4-difluoro-benzylamide)5-hydroxyamide

[0165] 66. thiophene-2,5-dicarboxylic acid 2-hydroxyamide5-[(3-imidazol-1-yl-propyl)-amide]

[0166] 67. thiophene-2,5-dicarboxylic acid2-[(1-cyclohexyl-ethyl)-amide]5-hydroxyamide

[0167] 68. thiophene-2,5-dicarboxylic acid2-[2-(3-chloro-phenyl)-ethyl]-amide 5-hydroxyamide

[0168] 69. thiophene-2,5-dicarboxylic acid2-[2-(3-fluoro-phenyl)-ethyl]-amide 5-hydroxyamide

[0169] 70. thiophene-2,5-dicarboxylic acid2-[2-(2,4-dichloro-phenyl)-ethyl]-amide 5-hydroxyamide

[0170] 71. thiophene-2,5-dicarboxylic acid 2-cyclopropylmethyl-amide5-hydroxyamide

[0171] 72. thiophene-2,5-dicarboxylic acid2-[2-(2-fluoro-phenyl)-ethyl]-amide 5-hydroxyamide

[0172] 73. thiophene-2,5-dicarboxylic acid2-[(4-diethylamino-1-methyl-butyl)-amide]5-hydroxyamide

[0173] 74. thiophene-2,5-dicarboxylic acid 2-hydroxyamide5-[(2-pyridin-2-yl-ethyl)-amide]

[0174] 75. thiophene-2,5-dicarboxylic acid 2-hydroxyamide5-[(2-pyrrolidin-1-yl-ethyl)-amide]

[0175] 76. thiophene-2,5-dicarboxylic acid 2-hydroxyamide5-[(1-methyl-hexyl)-amide]

[0176] 77. thiophene-2,5-dicarboxylic acid 2-cycloheptylamide5-hydroxyamide

[0177] 78. thiophene-2,5-dicarboxylic acid 2-cyclopentylamide5-hydroxyamide

[0178] 79. thiophene-2,5-dicarboxylic acid2-(2,4-dichloro-benzylamide)5-hydroxyamide

[0179] 80. thiophene-2,5-dicarboxylic acid2-[(3-diethylamino-propyl)-amide]5-hydroxyamide

[0180] 81. thiophene-2,5-dicarboxylic acid2-[(1,5-dimethyl-hexyl)-amide]5-hydroxyamide

[0181] 82. thiophene-2,5-dicarboxylic acid2-[(2,2-diphenyl-ethyl)-amide]5-hydroxyamide

[0182] 83. 3-[(5-hydroxycarbamoyl-thiophene-2-carbonyl)-amino]-butyricacid ethyl ester

[0183] 84. thiophene-2,5-dicarboxylic acid2-[(2-ethyl-hexyl)-amide]5-hydroxyamide

[0184] 85. thiophene-2,5-dicarboxylic acid 2-hydroxyamide5-(4-methoxy-benzylamide)

[0185] 86. thiophene-2,5-dicarboxylic acid 2-hydroxyamide5-(4-methyl-benzylamide)

[0186] 87. thiophene-2,5-dicarboxylic acid 2-hydroxyamide5-[(3-phenyl-propyl)-amide]

[0187] 88. thiophene-2,5-dicarboxylic acid2-[(2-diisopropylamino-ethyl)-amide]5-hydroxyamide

[0188] 89. thiophene-2,5-dicarboxylic acid 2-hydroxyamide5-[2-(4-nitro-phenyl)-ethyl]-amide

[0189] 90. thiophene-2,5-dicarboxylic acid2-[(3,3-diphenyl-propyl)-amide]5-hydroxyamide

[0190] 91. thiophene-2,5-dicarboxylic acid2-(2-amino-benzylamide)5-hydroxyamide

[0191] 92. Thiophene-2,5-dicarboxylic acid2-(4-bromo-benzylamide)5-hydroxyamide

[0192] 93. Thiophene-2,5-dicarboxylic acid2-(3,5-bis-trifluoromethyl-benzylamide) 5-hydroxyamide

[0193] 94. Thiophene-2,5-dicarboxylic acid2-(3-bromo-benzylamide)5-hydroxyamide

[0194] 95. Thiophene-2,5-dicarboxylic acid2-(3-fluoro-benzylamide)5-hydroxyamide

[0195] 96. Thiophene-2,5-dicarboxylic acid 2-hydroxyamide5-(3-methoxy-benzylamide)

[0196] 97. Thiophene-2,5-dicarboxylic acid2-(2-chloro-6-fluoro-benzylamide)5-hydroxyamide

[0197] 98. Thiophene-2,5-dicarboxylic acid2-(4-tert-butyl-benzylamide)5-hydroxyamide

[0198] 99. Thiophene-2,5-dicarboxylic acid 2-hydroxyamide5-{[2-(4-sulfamoyl-phenyl)-ethyl]-amide}

[0199] 100. Thiophene-2,5-dicarboxylic acid2-[(2-benzylsulfanyl-ethyl)-amide]5-hydroxyamide

[0200] 101. Thiophene-2,5-dicarboxylic acid 2-hydroxyamide5-{[2-(4-hydroxy-phenyl)-ethyl]-amide}

[0201] 102. Thiophene-2,5-dicarboxylic acid2-{[2-(4-chloro-phenyl)-ethyl]-amide}5-hydroxyamide

[0202] 103. Thiophene-2,5-dicarboxylic acid2-{[2-(3,4-dimethoxy-phenyl)-ethyl]-amide} 5-hydroxyamide

[0203] 104. Thiophene-2,5-dicarboxylic acid 2-hydroxyamide5-[(2-phenoxy-ethyl)-amide]

[0204] 105. Thiophene-2,5-dicarboxylic acid 2-hydroxyamide5-[(4-phenyl-butyl)-amide]

[0205] 106. Thiophene-2,5-dicarboxylic acid2-[(3,4-dimethyl-phenyl)-amide]5-hydroxyamide

[0206] 107.5-(4-Pyrimidin-2-yl-piperazine-1-carbonyl)-thiophene-2-carboxylic acidhydroxyamide

[0207] 108. Thiophene-2,5-dicarboxylic acid2-[(3,4-dimethoxy-phenyl)-amide]5-hydroxyamide

[0208] 109. Thiophene-2,5-dicarboxylic acid2-[(4-tert-butyl-phenyl)-amide]5-hydroxyamide

[0209] 110. Thiophene-2,5-dicarboxylic acid 2-hydroxyamide5-[(4-methoxy-2-methyl-phenyl)-amide]

[0210] 111. Thiophene-2,5-dicarboxylic acid2-[(4-dimethylamino-phenyl)-amide]5-hydroxyamide

[0211] 112. Thiophene-2,5-dicarboxylic acid 2-hydroxyamide5-[(4-phenoxy-phenyl)-amide]

[0212] 113. Thiophene-2,5-dicarboxylic acid 2-hydroxyamide5-p-tolylamide

[0213] 114. Thiophene-2,5-dicarboxylic acid 2-hydroxyamide5-[(4-piperidin-1-yl-phenyl)-amide]

[0214] 115.1-(5-Hydroxycarbamoyl-thiophene-2-carbonyl)-piperidine-4-carboxylic acidmethyl ester

[0215] 116. Thiophene-2,5-dicarboxylic acid 2-hydroxyamide5-[methyl-(1-methyl-piperidin-4-yl)-amide]

[0216] 117. Thiophene-2,5-dicarboxylic acid 2-hydroxyamide5-{methyl-[2-(4-nitro-phenyl)-ethyl]-amide}

[0217] 118. Thiophene-2,5-dicarboxylic acid2-(butyl-methyl-amide)5-hydroxyamide

[0218] 119. Thiophene-2,5-dicarboxylic acid 2-diethylamide5-hydroxyamide

[0219] 120. Thiophene-2,5-dicarboxylic acid2-[(4-cyclohexyl-phenyl)-amide]5-hydroxyamide

[0220] 121. Thiophene-2,5-dicarboxylic acid 2-hydroxyamide5-[methyl-(2-methylamino-ethyl)-amide]

[0221] 122. Thiophene-2,5-dicarboxylic acid2-[ethyl-(3-ethylamino-propyl)-amide]5-hydroxyamide

[0222] 123.5-[4-(2-Morpholin-4-yl-2-oxo-ethyl)-piperazine-1-carbonyl]-thiophene-2-carboxylicacid hydroxyamide

[0223] 124.5-(4-Dimethylcarbamoylmethyl-piperazine-1-carbonyl)-thiophene-2-carboxylicacid hydroxyamide

[0224] 125.5-[4-(2-Oxo-2-piperidin-1-yl-ethyl)-piperazine-1-carbonyl]-thiophene-2-carboxylicacid hydroxyamide

[0225] 126. Thiophene-2,5-dicarboxylic acid 2-hydroxyamide5-(3-trifluoromethoxy-benzylamide)

[0226] 127. Thiophene-2,5-dicarboxylic acid 2-hydroxyamide5-(3-phenoxy-benzylamide)

[0227] 128. Thiophene-2,5-dicarboxylic acid 2-hydroxyamide5-[(1-methyl-3-phenyl-propyl)-amide]

[0228] 129. Thiophene-2,5-dicarboxylic acid 2-hydroxyamide5-[(3-methoxy-propyl)-amide]

[0229] 130. Thiophene-2,5-dicarboxylic acid2-(4-chloro-benzylamide)5-hydroxyamide

[0230] 131. Thiophene-2,5-dicarboxylic acid2-[(2-acetylamino-ethyl)-amide]5-hydroxyamide

[0231] 132. Thiophene-2,5-dicarboxylic acid 2-hydroxyamide5-[(1-methyl-heptyl)-amide]

[0232] 133. Thiophene-2,5-dicarboxylic acid 2-hydroxyamide5-[(1-methyl-butyl)-amide]

[0233] 134. Thiophene-2,5-dicarboxylic acid 2-allylamide 5-hydroxyamide

[0234] 135. Thiophene-2,5-dicarboxylic acid2-[(1,3-dimethyl-butyl)-amide]5-hydroxyamide

[0235] 136. Thiophene-2,5-dicarboxylic acid 2-hydroxyamide 5-propylamide

[0236] 137. Thiophene-2,5-dicarboxylic acid 2-sec-butylamide5-hydroxyamide

[0237] 138. Thiophene-2,5-dicarboxylic acid 2-butylamide 5-hydroxyamide

[0238] 139. Thiophene-2,5-dicarboxylic acid2-(3,4-dichloro-benzylamide)5-hydroxyamide

[0239] 140. Thiophene-2,5-dicarboxylic acid2-(2,3-dichloro-benzylamide)5-hydroxyamide

[0240] 141. thiophene-2,5-dicarboxylic acid2-(2,3-difluoro-benzylamide)5-hydroxyamide

[0241] 142. thiophene-2,5-dicarboxylic acid2-(2-chloro-benzylamide)5-hydroxyamide

[0242] 143. thiophene-2,5-dicarboxylic acid2-(3,4-dimethoxy-benzylamide)5-hydroxyamide

[0243] 144. thiophene-2,5-dicarboxylic acid2-(3,5-difluoro-benzylamide)5-hydroxyamide

[0244] 145. thiophene-2,5-dicarboxylic acid2-[(2-amino-phenyl)-amide]5-hydroxyamide

[0245] 146. thiophene-2,5-dicarboxylic acid2-[4-(2-amino-phenylcarbamoyl)-benzylamide]5-(benzyloxy-amide)

[0246] 147. thiophene-2,5-dicarboxylic acid 2-hydroxyamide5-[methyl-(4-trifluoromethyl-benzyl)-amide]

EXAMPLE 16

[0247] In an analogous manner to that described in the example 3, andusing known methods as described in the literature (e.g. in standardworks such as Houben-Weyl, “Methoden der Organischen Chemie, GeorgThieme Verlag”, Stuttgart; Organic Reactions, John Wiley & Sons, Inc.,New York) the following compounds are prepared and characterized with MS(APCI):

[0248] 1. 4-(4-benzhydryl-piperazine-1-carbonyl)-N-hydroxy-benzamide

[0249] 2. N-hydroxy-N′-pyridin-3-ylmethyl-terephthalamide

[0250] 3. N-benzyl-N′-hydroxy-terephthalamide

[0251] 4. N-cyclohexyl-N′-hydroxy-terephthalamide

[0252] 5. N-cyclopropyl-N′-hydroxy-terephthalamide

[0253] 6. N-hexyl-N′-hydroxy-terephthalamide

[0254] 7. N-hydroxy-N′-(3-methyl-butyl)-terephthalamide

[0255] 8. N-hydroxy-N′-phenethyl-terephthalamide

[0256] 9. N-hydroxy-N′-[2-(4-methoxy-phenyl)-ethyl]-terephthalamide

[0257] 10. N-(3-chloro-benzyl)-N′-hydroxy-terephthalamide

[0258] 11. N-hydroxy-N′-(2-methoxy-benzyl)-terephthalamide

[0259] 12. N-(4-fluoro-benzyl)-N′-hydroxy-terephthalamide

[0260] 13.N-hydroxy-N′-(1,2,3,4-tetrahydro-naphthalen-1-yl)-terephthalamide

[0261] 14. N-hydroxy-N′-(4-trifluoromethyl-benzyl)-terephthalamide

[0262] 15. N-(2,4-difluoro-benzyl)-N′-hydroxy-terephthalamide

[0263] 16. N-hydroxy-N′-indan-1-yl-terephthalamide

[0264] 17. N-benzo [1,3]dioxol-5-ylmethyl-N′-hydroxy-terephthalamide

[0265] 18. N-hydroxy-4-(4-phenyl-piperazine-1-carbonyl)-benzamide

[0266] 19. N-(3,5-dimethyl-benzyl)-N′-hydroxy-terephthalamide

[0267] 20. N-hydroxy-N′-(3-isopropoxy-propyl)-terephthalamide

[0268] 21. 4-(4-acetyl-piperazine-1-carbonyl)-N-hydroxy-benzamide

[0269] 22. N,N-dibutyl-N′-hydroxy-terephthalamide

[0270] 23. 4-(4-benzyl-piperidine-1-carbonyl)-N-hydroxy-benzamide

[0271] 24.N-hydroxy-N′-[2-(1-methyl-pyrrolidin-2-yl)-ethyl]-terephthalamide

[0272] 25. N-(2-ethoxy-benzyl)-N′-hydroxy-terephthalamide

[0273] 26. N-(2-cyclohex-1-enyl-ethyl)-N′-hydroxy-terephthalamide

[0274] 27. N-hydroxy-N′-(2-morpholin-4-yl-ethyl)-terephthalamide

[0275] 28. N-hydroxy-N′-(2-methylsulfanyl-ethyl)-terephthalamide

[0276] 29. N-hydroxy-N′-(tetrahydro-furan-2-ylmethyl)-terephthalamide

EXAMPLE 17 Evaluation of Effects on a Human Colon Caminoma Cell Line ofthe Compounds of the Invention

[0277] MTT (tetrazolium dye proliferation assay) is widely used for thequantitative determination of cytotoxic effects or in vitrochemosensitivity of tumor cells. The assay is based on the cleavage ofthe yellow tetrazolium salt MTT to purple formazan crystals by metabolicactive cells. For details, see Rubinstein, L. V., et al., J. Natl.Cancer Inst. 82 (1990) 1113-1118.

[0278] The following procedure was performed: HT-29 cells (human coloncarcinoma cell line) were cultivated in RPMI 1640, 2.5% FCS, 2 mMGlutamine, 100 u/ml Penicillin, 100 ug/ml Streptomycin. For the assaythe cells were seeded in 384 well plates, 900 cells per well, in thesame medium The next day compounds (dissolved 10 mM in DMSO) were addedin various concentrations ranging from 30 uM to 1.5 nM. After 5 days theMTT assay was done mainly according to the instructions of themanufacturer (Cell proliferation kit I, MTT, fom Roche MolecularBiochemicals). In brief: MTT labeling reagent was added to a finalconcentration of 0.5 mg/ml, added and incubated for 4 hrs at 37 C, 5%CO₂. During this incubation time purple formazan crystals are formed.After addition of the solubilization solution (20% SDS in 0.02 M HCl)the plates were incubated overnight at 37 C, 5% CO₂. After carefulmixing plates were measured in Victor 2 (scanning multiwellspectrophotometer, Wallac) at 550 nm.

[0279] A decrease in number of living cells results in a decrease in thetotal metabolic activity in the sample. The decrease directly correlatesto the amount of purple colour resulting from the solubilization of thepurple formazan crystals. Determination of IC50 was done using XL-fit.The results of this experiment are provided below in Table 1. TABLE 1Compounds according to this invention IC50 HT29 [μM] Example 15, No.128  0.02 Example 15, No. 81 0.03 Example 15, No. 104  0.04 Example 50.05 Example 15, No. 93 0.05 Example 15, No. 94 0.07 Example 15, No. 980.07 Example 2 0.11 Example 4 0.14 Example 15, No. 90 0.14 Example 15,No. 139  0.17

EXAMPLE 18

[0280] Tablet formulation Item Ingredients mg/Tablet 1 Compound 2a 25100 2 Anhydrous Lactose 73 35 3 Croscarmellose 6 8 Sodium 4 Povidone K305 6 5 Magnesium Stearate 1 1 Total Weight 110 150

[0281] Compound 2a is described in Example 2.

[0282] Procedure:

[0283] 1. Mix Items 1, 2 and 3 in a suitable mixer for 15 minutes.

[0284] 2. Granulate the powder mix from Step 1 with 20% Povidone K30Solution (Item 4).

[0285] 3. Dry the granulation from Step 2 at 50° C.

[0286] 4. Pass the granulation from Step 3 through a suitable millingequipment.

[0287] 5. Add the Item 5 to the milled granulation Step 4 and mix for 3minutes.

[0288] 6. Compress the granulation from Step 5 on a suitable press.

LIST OF REFERENCES

[0289] Cancer: Principles & Practice of Oncology, Vincent T. DeVita,Jr., Samuel Hellmann, Steven A. Rosenberg; 5th Ed., Lippincott-RavenPublishers 1997

[0290] Houben-Weyl, “Methoden der Organischen Chemie, Georg ThiemeVerlag”, Stuttgart; Organic Reactions, John Wiley & Sons, Inc., New York

[0291] Houben-Weyl, Methoden der organischen Chemie, Vol. XV/1 and XV/2

[0292] Koyama, Y., et al., Blood 96 (2000) 1490-1495

[0293] Marks, P. M., et al., J. Natl. Cancer Inst. 92 (2000) 1210-1216

[0294] Org. Prep. and Proced. Int. 3 (6) (1971) 295

[0295] Rubinstein, L. V., et al., J. Natl. Cancer Inst. 82 (1990)1113-1118

[0296] U.S. Pat. No. 2,680,731

[0297] U.S. Pat. No. 5,369,108

[0298] WO 98/55449

[0299] Z. Phys. Chem.(Leipzig) 262 (3) (1981) 445-448

1. A compound of formula I

is a phenyl ring that may be unsubstituted or substituted by 1, 2 or 3substituents independently selected from halogen, C₁₋₄-alkyl-,trifluoromethyl-, hydroxy-, C₁₋₄-alkoxy-, nitro-, amino-,C₁₋₄-alkylamino-, di[C₁₋₄-alkyl]-amino-, C₁₋₄-alkanoylamino,C₁₋₃-alkylenedioxy or an acyl group;  and R1 and R2 are eachindependently selected from hydrogen, a branched or unbranchedC₁₋₁₄-alkyl group that may be unsubstituted or substituted with 1 ormore substituents independently selected from halogen, hydroxy-, nitro-,an amino group, a carbocyclic group or a heterocyclic group, and whereinat a chain length of longer than 2 carbon atoms, one or more nonadjacent atoms may be replaced by oxygen, nitrogen or sulfur atoms, andwherein 2 atoms may be bound together by a double or triple bond, acarbocyclic group, and a heterocyclic group, or alternatively, the group—NR¹R² forms a 3-6 membered ring that may contain additional heteroatomsindependently selected from nitrogen, oxygen and sulfur, said ringoptionally being annulated to a carbocyclic ring or a heterocyclic ring,and said —NR¹R² ring being unsubstituted or optionally substituted by 1,2, or 3 substituents independently selected from a halogen atom, anC₁₋₄-alkyl-, trifluoromethyl-, hydroxy-, C₁₋₄-alkoxy-, aryl-, hetaryl-,arylalkyl, arylalkyloxy-, aryloxy, C₁₋₃-alkylenedioxy-, nitro-, amino-,C₁₋₄-alkylamino-, di[C₁₋₄-alkyl]amino-, C₁₋₄-alkanoylamino- or anacyl-group; or the enantiomers, diastereoisomers, racemates andphysiologically acceptable salts thereof.
 2. The compound of claim 1wherein R² is benzyl or substituted benzyl.
 3. The compound of claim 1wherein R² is benzyl or substituted benzyl.
 4. A compound selected fromthe group consisting ofN-hydroxy-N′-naphthalen-1-ylmethyl-terephthalamide;4-(4-benzhydryl-piperazine-1-carbonyl)-N-hydroxy-benzamide;N-hydroxy-N′-pyridin-3-ylmethyl-terephthalamide;N-benzyl-N′-hydroxy-terephthalamide;N-cyclohexyl-N′-hydroxy-terephthalamide;N-cyclopropyl-N′-hydroxy-terephthalamide;N-hexyl-N′-hydroxy-terephthalamide;N-hydroxy-N′-(3-methyl-butyl)-terephthalamide;N-hydroxy-N′-phenethyl-terephthalamide; andN-hydroxy-N′-[2-(4-methoxy-phenyl)-ethyl]-terephthalamide.
 5. A compoundselected from the group consisting ofN-(3-chloro-benzyl)-N′-hydroxy-terephthalamide;N-hydroxy-N′-(2-methoxy-benzyl)-terephthalamide;N-(4-fluoro-benzyl)-N′-hydroxy-terephthalamide;N-hydroxy-N′-(1,2,3,4-tetrahydro-naphthalen-1-yl)-terephthalamide;N-hydroxy-N′-(4-trifluoromethyl-benzyl)-terephthalamide;N-(2,4-difluoro-benzyl)-N′-hydroxy-terephthalamide;N-hydroxy-N′-indan-1-yl-terephthalamide; N-benzo[1,3]dioxol-5-ylmethyl-N′-hydroxy-terephthalamide;N-hydroxy-4-(4-phenyl-piperazine-1-carbonyl)-benzamide; andN-(3,5-dimethyl-benzyl)-N′-hydroxy-terephthalamide.
 6. A compoundselected from the group consisting ofN-hydroxy-N′-(3-isopropoxy-propyl)-terephthalamide;4-(4-acetyl-piperazine-1-carbonyl)-N-hydroxy-benzamide;N,N-dibutyl-N′-hydroxy-terephthalamide;4-(4-benzyl-piperidine-1-carbonyl)-N-hydroxy-benzamide;N-hydroxy-N′-[2-(1-methyl-pyrrolidin-2-yl)-ethyl]-terephthalamide;N-(2-ethoxy-benzyl)-N′-hydroxy-terephthalamide;N-(2-cyclohex-1-enyl-ethyl)-N′-hydroxy-terephthalamide;N-hydroxy-N′-(2-morpholin-4-yl-ethyl) terephthalamide;N-hydroxy-N′-(2-methylsulfanyl-ethyl)-terephthalamide; andN-hydroxy-N′-(tetrahydro-furan-2-ylmethyl)-terephthalamide.
 7. A processof manufacturing a compound of formula I comprising reacting a compoundof formula III

 with an amine of the formula HNR₁R₂ in the presence of an activatingagent, to give a compound of formula II

 reacting the compound of formula II with hydroxylamine in the presenceof a suitable base, wherein

 is a phenyl ring that may be unsubstituted or substituted by 1, 2 or 3substituents independently selected from halogen, a C₁₋₄-alkyl-,trifluoromethyl-, hydroxy-, C₁₋₄-alkoxy-, nitro-, amino-,C₁₋₄-alkylamino-, di[C₁₋₄-alkyl]-amino-, C₁₋₄-alkanoylamino, aC₁₋₃-alkylenedioxy-group or an acyl group; R1 and R2 are eachindependently selected from hydrogen, a branched or unbranchedC₁₋₁₄-alkyl group that may be unsubstituted or substituted with 1 ormore substituents independently selected from halogen, hydroxy-, nitro-,an amino group, a carbocyclic group or a heterocyclic group, and whereinat a chain length of longer than 2 carbon atoms, one or more nonadjacent atoms may be replaced by oxygen, nitrogen or sulfur atoms, andwherein 2 atoms may be bound together by a double or triple bond, acarbocyclic group, and a heterocyclic group, or alternatively, the group—NR¹R² forms a 3-6 membered ring that may contain additional heteroatomsindependently selected from nitrogen, oxygen and sulfur, said ringoptionally being annulated to a carbocyclic ring or a heterocyclic ring,and said —NR¹R² ring being unsubstituted or optionally substituted by 1,2, or 3 substituents independently selected from a halogen atom, anC₁₋₄-alkyl-, trifluoromethyl-, hydroxy-, C₁₋₄-alkoxy-, aryl-, hetaryl-,arylalkyl, arylalkyloxy-, aryloxy, C₁₋₃-alkylenedioxy-, nitro-, amino-,C₁₋₄-alkylamino-, di[C₁₋₄-alkyl]amino-, C₁₋₄-alkanoylamino- or anacyl-group; and R3 is C₁₋₄-alkyl.
 8. A pharmaceutical compositioncomprising a therapeutically effective amount of a compound of claim 1and a pharmaceutically acceptable carrier or excipient.
 9. A method oftreating breast, lung, colon, rectal, stomach, prostate, bladder,pancreas or ovarian cancer comprising administering to a subject in needof such treatment a therapeutically effective amount of a compound ofclaim
 1. 10. A compound of formula

is a phenyl ring that may be unsubstituted or substituted by 1, 2 or 3substituents independently selected from halogen, a C₁₋₄-alkyl-,trifluoromethyl-, hydroxy-, C₁₋₄-alkoxy-, nitro-, amino-,C₁₋₄-alkylamino-, di[C₁₋₄-alkyl]-amino-, C₁₋₄-alkanoylamino, aC₁₋₃-alkylenedioxy-group or an acyl group; R1 and R2 are eachindependently selected from hydrogen, a branched or unbranchedC₁₋₁₄-alkyl group that may be unsubstituted or substituted with 1 ormore substituents independently selected from halogen, hydroxy-, nitro-,an amino group, a carbocyclic group or a heterocyclic group, and whereinat a chain length of longer than 2 carbon atoms, one or more nonadjacent atoms may be replaced by oxygen, nitrogen or sulfur atoms, andwherein 2 atoms may be bound together by a double or triple bond, acarbocyclic group, and a heterocyclic group, or alternatively, the group—NR¹R², forms a 3-6 membered ring that may contain additionalheteroatoms independently selected from nitrogen, oxygen and sulfur,said ring optionally being annulated to a carbocyclic ring or aheterocyclic ring, and said —NR1R² ring being unsubstituted oroptionally substituted by 1, 2, or 3 substituents independently selectedfrom a halogen atom, an C₁₋₄-alkyl-, trifluoromethyl-, hydroxy-,C₁₋₄-alkoxy-, aryl-, hetaryl-, arylalkyl, arylalkyloxy-, aryloxy,C₁₋₃-alkylenedioxy-, nitro-, amino-, C₁₋₄-alkylamino-,di[C₁₋₄-alkyl]amino-, C₁₋₄-alkanoylamino- or an acyl-group; and Y is aprotecting group.